Polymorphs of a pges-1 inhibiting triazolone compound

ABSTRACT

The present application relates to solid state forms of a triazolone compound which exhibit mPGES-1 enzyme inhibition activity, specifically N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl) pivalamide (Compound of formula II), and process for preparation thereof.

RELATED APPLICATIONS

This application claims the benefit of Indian Provisional ApplicationNo. 2275/MUM/2015 filed on Jun. 12, 2015, which is hereby incorporatedby reference in its entirety.

TECHNICAL FILED OF THE INVENTION

The present application relates to solid state forms of a triazolonecompound which exhibit mPGES-1 enzyme inhibition activity, specificallyN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, and process for preparation thereof.

BACKGROUND OF THE INVENTION

There are many diseases or disorders that are inflammatory in theirnature. One of the major problems associated with existing treatments ofinflammatory conditions is inadequate efficacy and/or the prevalence ofside effects. Inflammatory diseases that affect the population includeasthma, inflammatory bowel disease, rheumatoid arthritis,osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation isalso a common cause of pain.

The enzyme cyclooxygenase (COX) converts arachidonic acid to an unstableintermediate, prostaglandin H₂ (PGH₂), which is further converted toother prostaglandins, including PGE₂, PGF₂a, PGD₂, prostacyclin andthromboxane A₂. These arachidonic acid metabolites are known to havepronounced physiological and pathophysiological activity, includingpro-inflammatory effects. The COX enzyme exists in two forms, one thatis constitutively expressed in many cells and tissues (COX-1), andanother that in mast cells and tissues is induced by pro-inflammatorystimuli, such as cytokines, during an inflammatory response (COX-2).

Among all prostaglandin metabolites, PGE₂ is particularly known to be astrong pro-inflammatory mediator, and is also known to induce fever andpain. Consequently, numerous drugs have been developed with a view toinhibiting the formation of PGE₂, including “NSAIDs” (non-steroidalanti-inflammatory drugs) and “coxibs” (selective COX-2 inhibitors).These drugs act predominantly by inhibition of COX-1 and/or COX-2,thereby reducing the formation of PGE₂. However, the inhibition of COXshas the disadvantage of reducing the formation of all metabolites ofPGH₂, thereby decreasing the beneficial properties of some of themetabolites. In view of this, drugs which act by inhibition of COXs aresuspected to cause adverse biological effects. For example, thenon-selective inhibition of COXs by NSAIDs may give rise togastrointestinal side-effects and affect platelet and renal function.Even the selective inhibition of COX-2 by coxibs, whilst reducing suchgastrointestinal side-effects, is believed to give rise tocardiovascular problems.

A combination of pharmacological, genetic and neutralizing antibodyapproaches demonstrates the importance of PGE₂ in inflammation. Theconversion of PGH₂ to PGE₂ by prostaglandin E synthases (PGES) may,therefore, represent a pivotal step in the propagation of inflammatorystimuli. There are two microsomal prostaglandin E synthases (mPGES-1 andmPGES-2), and one cytosolic prostaglandin E synthase (cPGES). mPGES-1 isan inducible PGES after exposure to pro-inflammatory stimuli. mPGES-1 isinduced in the periphery and CNS by inflammation, and representstherefore a target for acute and chronic inflammatory disorders. PGE₂ isa major prostanoid, produced from arachidonic acid liberated byphospholipases (PLAs), which drives the inflammatory processes.Arachidonic acid is transformed by the action of prostaglandin Hsynthase (PGH synthase, cycloxygenase) into PGH₂ which is a substratefor mPGES-1, the terminal enzyme transforming PGH₂ to thepro-inflammatory PGE₂.

Agents that are capable of inhibiting the action of mPGES-1, and thusreducing the formation of the specific arachidonic acid metabolite PGE₂,are beneficial in the treatment of inflammation. Further, agents thatare capable of inhibiting the action of the proteins involved in thesynthesis of the leukotrienes are also beneficial in the treatment ofasthma and COPD.

Blocking the formation of PGE₂ in animal models of inflammatory painresults in reduced inflammation, pain and fever response (Kojima et. al,The Journal of Immunology 2008, 180, 8361-6; Xu et. al., The Journal ofPharmacology and Experimental Therapeutics 2008, 326, 754-63). Inabdominal aortic aneurism, inflammation leads to connective tissuedegradation and smooth muscle apoptosis ultimately leading to aroticdilation and rupture. In animals lacking mPGES-1 a slower diseaseprogression and disease severity has been demonstrated (Wang et. al.,Circulation, 2008, 117, 1302-1309).

Several lines of evidence indicate that PGE₂ is involved in malignantgrowth. PGE₂ facilitates tumor progression by stimulation of cellularproliferation and angiogenesis and by modulation of immunosupression. Insupport of a role for PGE₂ in cancers, genetic deletion of mPGES-1 inmice suppresses intestinal tumourogenesis (Nakanishi et. al., CancerResearch 2008, 68(9), 3251-9). In human beings, mPGES-1 is alsoupregulated in cancers such as colorectal cancer (Schroder, Journal ofLipid Research 2006, 47, 1071-80).

International Publication Number WO 2013/186692 discloses triazolonecompounds of formula (I) (disclosed as formula (III) in thespecification of WO 2013/186692)

wherein,

X¹, X² and X³ are each independently selected from CH and N;

P is selected from —CH₂NHC(O)— and —CH₂NHS(O)₂—;

Q is selected from C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxyC₁₋₈alkyl,hydroxyC₁₋₈alkyl, carboxylC₁₋₈alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₄aryl, 3-15membered heterocyclyl, and 5-14 membered heteroaryl;

each occurrence of R¹ is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

each occurrence of R² is independently selected from halogen, cyano,C₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkyl, C₃₋₆cycloalkyl, 5 memberedheteroaryl, —C(O)NHR, —NHC(O)R, —S(O)₂NHR and —C≡CR;

each occurrence of R is independently selected from C₁₋₈alkyl,C₃₋₁₂cycloalkyl, and C₆₋₁₄aryl;

‘m’ is an integer ranging from 0 to 3, both inclusive; and

‘n’ is an integer ranging from 0 to 3, both inclusive;

with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.

The compounds of formula (I) exhibit mPGES-1 enzyme inhibition activityand, therefore, are useful for the treatment of pain and inflammation ina variety of diseases or conditions.

The compound“N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide”,herein after designated as “compound of formula (II)” is disclosed asExample 100 in the specification of WO 2013/186692. Also disclosedtherein, is the process for preparation of compound of formula (II). Thestructural representation of compound of formula (II) is

Development of a commercial drug candidate involves many steps, such asdevelopment of a cost effective synthetic method which is efficient inlarge scale manufacturing process. Also, in formulation of drugcompositions, it is important for the active pharmaceutical ingredientto be in a form in which it can be conveniently handled and processed.Convenient handling is important not only from the perspective ofobtaining a commercially viable manufacturing process, but also from theperspective of subsequent manufacture of pharmaceutical formulationscomprising the active pharmaceutical ingredient. The drug developmenttherefore involves research regarding finding suitable pharmaceuticallyacceptable salt forms of a drug. It may be also desirable to explorevarious polymorphs of the active pharmaceutical ingredient, whichdisplay better handling properties as well as it may also show improvedphysicochemical as well as pharmacokinetic and pharmacodynamicsproperties.

SUMMARY OF THE INVENTION

The present application relates to novel solid state forms of compoundof formula (II). Further the present application relates to an improvedprocess for the manufacture of compound of formula (II) which issuitable for large scale synthesis. The process of the presentapplication involves less number of steps and also provides the compoundof formula (II) in high yield and with high purity.

In one aspect, the present application relates toN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,represented by formula (II) in solid state form.

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,herein after designated as compound of formula (II).

In an embodiment, the solid state forms of compound of formula (II)exist in an anhydrous and/or solvent-free form or as a hydrate and/or asolvate form.

In another embodiment, the present invention relates to crystalline formof compound of formula (II).

In another embodiment, the present invention relates to crystalline formof compound of formula (II) which is designated as Form I.

In yet another embodiment, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form I.

In another embodiment the present invention relates to crystalline formof compound of formula (II) which is designated as Form II.

In yet another embodiment, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form II.

In another embodiment the present invention relates to crystalline formof compound of formula (II) which is designated as Form III.

In yet another embodiment, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form III.

In an embodiment of the present invention, the various crystalline formsof the invention are in substantially pure crystalline forms. For thepurpose of the present invention, the term “substantially pure” as usedherein includes reference to crystalline forms of, or greater than, 90%,more preferably 95%, more preferably 97%, more preferably 99%polymorphic purity as determined, for example by X-ray powderdiffraction, Raman spectroscopy or IR spectroscopy.

In yet another embodiment the present invention relates to crystallineform of compound of formula (II), which is a mixture of any two or moreforms of compound of formula (II), designated as Form I, Form II andForm III.

In another aspect of the application there is provided an amorphous formofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (compound of formula (II)).

In yet another embodiment, the present invention relates to process forpreparing compound of formula (II) in amorphous form.

In another embodiment, there is provided a method for treating diseases,conditions and/or disorders modulated by mPGES-1 enzyme; comprisingadministering a crystalline form of compound of formula (II), or apharmaceutical composition that comprises the crystalline form ofcompound of formula (II) along with pharmaceutically acceptableexcipients.

In another embodiment, there is provided a method for treating diseases,conditions and/or disorders modulated by mPGES-1 enzyme; comprisingadministering a crystalline form of compound of formula (II) designatedas Form (I), or a pharmaceutical composition that comprises thecrystalline form of compound of formula (II) designated as Form (I),along with pharmaceutically acceptable excipients.

In another embodiment, there is provided a method for treating diseases,conditions and/or disorders modulated by mPGES-1 enzyme; comprisingadministering a crystalline form of compound of formula (II) designatedas Form (II), or a pharmaceutical composition that comprises thecrystalline form of compound of formula (II) designated as Form (II),along with pharmaceutically acceptable excipients.

In another embodiment, there is provided a method for treating diseases,conditions and/or disorders modulated by mPGES-1 enzyme; comprisingadministering a crystalline form of compound of formula (II) designatedas Form (III), or a pharmaceutical composition that comprises thecrystalline form of compound of formula (II) designated as Form (III),along with pharmaceutically acceptable excipients.

In another embodiment, there is provided crystalline compound of formula(II) having an average particle size value (D₅₀) in the range from about1 μm to about 100 μm.

In yet another embodiment, there is provided the crystalline compound offormula (II) having an average particle size value (D₅₀) in range fromabout 1 μm to about 50 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having an average particle size value (D₅₀) in the rangefrom about 1 μm to about 20 μm.

In another embodiment, there is provided crystalline compound of formula(II) having a D₁₀ value in the range from about 0.3 μm to about 10 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₁₀ value in the range from about 0.5 μm to about8 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₁₀ value in the range from about 0.5 μm to about5 μm.

In another embodiment, there is provided crystalline compound of formula(II) having a D₉₀ value in the range from about 4 μm to about 300 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₉₀ value in the range from about 5 μm to about250 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₉₀ value in the range from about 5 μm to about200 μm.

In yet another embodiment, there is provided the compound of formula(II) having a D₉₀ value in the range from about 5 μm to about 150 μm.

In another aspect of the application there is provided substantiallypureN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide(compound of formula (II)). For the purpose of the present invention,the term “substantially pure” as used herein includes reference topurity of, or greater than, 98%, more preferably 99%, more preferably99.5%, more preferably 99.9% purity as determined, for example by HPLC.

In yet another embodiment, the present invention relates tosubstantially pure compound of formula (II) having purity greater thanabout 98% by HPLC.

In yet another embodiment, the present invention relates tosubstantially pure compound of formula (II) having purity greater thanabout 99% by HPLC.

In yet another embodiment, the present invention relates tosubstantially pure compound of formula (II) having purity greater thanabout 99.9% by HPLC.

In yet another embodiment, three is provided compound of formula (II)which is substantially free from the impurity represented by compound offormula (II′).

For the purpose of this invention, the term “substantially free” as usedherein includes reference to presence of impurity of, or less than, 2%,more preferably 1%, more preferably 0.5%, more preferably 0.1% impurityas determined, for example by HPLC.

In yet another aspect of the application, there is provided an improvedprocess for preparation of compound of formula (II) or itspharmaceutically acceptable salts.

In an embodiment, the present application relates to process forpreparation of compound of formula (II) or salt thereof

wherein the compound of formula (II) is prepared from compound offormula (III)

In yet another embodiment, there is provided process for preparation ofcompound of formula (II) or salt thereof, which process comprising thestep of reacting compound of formula (IV)

with oxalyl chloride and compound of formula (V)

to obtain compound of formula (III)

In yet another embodiment there is provided process for the preparationof compound of formula (II) or salt thereof, which process comprises thesteps of:

-   -   a) reacting 2-chloro benzoic acid with        2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain        substantially pure compound of formula (VI);

-   -   b) converting compound of formula (VI) to compound of formula        (IV);

-   -   c) reacting compound of formula (IV) with oxalyl chloride and        compound of formula (V)

to obtain compound of formula (III);

-   -   d) converting compound of formula (III) to compound of formula        (II).

In another embodiment, there is provided process for preparation ofcompound of formula (II) or salt thereof, which process comprising thestep of reacting 2-chloro benzoic acid with a compound (VII)

to obtain compound of formula (VIa)

wherein R is chloro, bromo or methyl. In this embodiment, compound (VII)can be selected from 2,2,2-Trichloro-N-(hydroxymethyl)acetamide,2,2,2-Tribromo-N-(hydroxymethyl) acetamide or2,2,2-Trimethyl-N-(hydroxymethyl)acetamide.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is powder X-ray diffraction pattern of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,designated as Form I.

FIG. 2 is Infra-Red (IR) spectra of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,designated as Form I.

FIG. 3 is powder X-ray diffraction pattern of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,designated as Form II.

FIG. 4 is Infra-Red (IR) spectra of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,designated as Form II.

FIG. 5 is powder X-ray diffraction pattern of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,designated as Form III.

FIG. 6 is Infra-Red (IR) spectra of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,designated as Form III.

FIG. 7 is powder X-ray diffraction pattern of amorphous form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present application relates toN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,represented by formula (II) in solid state form.

In an embodiment, the solid state forms of compound of formula (II)exist in an anhydrous and/or solvent-free form or as a hydrate and/or asolvate form.

In another embodiment, the present invention relates to solid state formof compound of formula (II) which is crystalline.

In another embodiment, the present invention relates to crystalline formcompound of formula (II) which is designated as Form I.

In yet another embodiment, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form I.

In another embodiment the present invention relates to crystalline formof compound of formula (II) which is designated as Form II.

In yet another embodiment, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form II.

In another embodiment the present invention relates to crystalline formof compound of formula (II) which is designated as Form III.

In yet another embodiment, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form III.

In an embodiment of the present invention, the various crystalline formsof the invention are in substantially pure crystalline forms. For thepurpose of the present invention, the term “substantially pure” as usedherein includes reference to crystalline forms of, or greater than, 90%,more preferably 95%, more preferably 97%, more preferably 99%polymorphic purity as determined, for example by X-ray powderdiffraction, Raman spectroscopy or IR spectroscopy.

In another aspect of the application there is providedN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide(compound of formula (II)) in amorphous form.

In yet another embodiment, the present invention relates to process forpreparing compound of formula (II) in amorphous form.

In yet another aspect of the application there is provided substantiallypureN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide(compound of formula (II)). For the purpose of the present invention,the term “substantially pure” as used herein includes reference topurity of, or greater than, 98%, more preferably 99%, more preferably99.5%, more preferably 99.9% purity as determined, for example by HPLC.

In yet another embodiment, the present invention relates tosubstantially pure compound of formula (II) having purity greater thanabout 98% by HPLC.

In yet another embodiment, the present invention relates tosubstantially pure compound of formula (II) having purity greater thanabout 99% by HPLC.

In yet another embodiment, the present invention relates tosubstantially pure compound of formula (II) having purity greater thanabout 99.9% by HPLC.

In yet another embodiments provided compound of formula (II) which issubstantially free from the impurity represented by compound of formula(II′).

For the purpose of this invention, the term “substantially free” as usedherein includes reference to presence of impurity of, or less than, 2%,more preferably 1%, more preferably 0.5%, more preferably 0.1% impurityas determined, for example by HPLC.

In another embodiment, there is provided crystalline compound of formula(II) having an average particle size value (D₅₀) in the range from about1 μm to about 100 μm.

In yet another embodiment, there is provided the crystalline compound offormula (II) having an average particle size value (D₅₀) in range fromabout 1 μm to about 50 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having an average particle size value (D₅₀) in the rangefrom about 1 μm to about 20 μm.

In another embodiment, there is provided crystalline compound of formula(II) having a D₁₀ value in the range from about 0.3 μm to about 10 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₁₀ value in the range from about 0.5 μm to about8 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₁₀ value in the range from about 0.5 μm to about5 μm.

In another embodiment, there is provided crystalline compound of formula(II) having a D₉₀ value in the range from about 4 μm to about 300 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₉₀ value in the range from about 5 μm to about250 μm.

In yet another embodiment, there is provided crystalline compound offormula (II) having a D₉₀ value in the range from about 5 μm to about200 μm.

In yet another embodiment, there is provided the compound of formula(II) having a D₉₀ value in the range from about 5 μm to about 150 μm.

The particle size characteristic for compound of formula (II) for someof the batches is provided in Table 1.

TABLE 1 Particle size Batch. No d (0.1) μm d (0.5) μm d (0.9) μm 1 0.73.7 12.7 2 0.6 2.0 9.0 3 0.7 3.3 14.8 4 0.7 2.4 10.7 5 0.7 2.2 9.4

In another embodiment, the present invention relates to crystalline formof compound of formula (II) which is designated as Form I.

In yet another embodiment, Form I of compound of formula (II) ischaracterized by the X-Ray Powder Diffraction (XRPD) pattern as shown inFIG. 1.

In yet another embodiment, Form I of compound of formula (II) is furthercharacterized by the characteristic X-ray diffraction pattern comprisingof the following peaks expressed in terms of 2θ±0.2: 5.66, 6.55 and13.05.

In yet another embodiment, Form I of compound of formula (II) is furthercharacterized by the characteristic X-ray diffraction pattern comprisingof the following peaks expressed in terms of 2θ±0.2: 5.66, 6.55, 12.51,13.05, 15.01, 16.59 and 25.69.

In yet another embodiment, Form I of compound of formula (II) is furthercharacterized by the characteristic X-ray diffraction pattern peaksexpressed in terms of 20 as presented in Table 2.

TABLE 2 Prominent two theta positions and relative intensities of XRPDof Form I of compound of formula (II) Angle (2θ ± 0.2) Relativeintensity (%) 5.07 21.13 5.66 28.35 6.55 7.22 6.99 41.72 8.82 29.5212.51 100.00 13.05 11.12 14.48 6.01 15.01 17.96 16.59 42.13 16.81 29.6417.56 6.69 18.28 24.69 20.00 7.05 20.53 11.23 21.59 9.41 22.55 9.4224.46 7.20 25.69 24.98 26.14 9.03 26.45 9.27 27.07 8.83 28.23 7.56

In yet another embodiment, Form I of compound of formula (II) ischaracterized by the Fourier Transform Infrared Spectroscopy (FT-IR)pattern as shown in FIG. 2.

In another embodiment, the present invention relates to crystalline formof compound of formula (II) which is designated as Form II.

In yet another embodiment, Form II of compound of formula (II) ischaracterized by the X-Ray Powder Diffraction (XRPD) pattern as shown inFIG. 3.

In yet another embodiment, Form II of compound of formula (II) isfurther characterized by the characteristic X-ray diffraction patterncomprising of the following peaks expressed in terms of 2θ±0.2: 24.57and 30.85.

In yet another embodiment, Form II of compound of formula (II) isfurther characterized by the characteristic X-ray diffraction patterncomprising of the following peaks expressed in terms of 2θ±0.2: 7.02,12.54, 16.64, 18.31, 24.57, 25.74 and 30.85.

In yet another embodiment, Form II of compound of formula (II) isfurther characterized by the characteristic X-ray diffraction patternpeaks expressed in terms of 20 as presented in Table 3.

TABLE 3 Prominent two theta positions and relative intensities of XRPDof Form II of compound of formula (II) Angle (2θ ± 0.2) Relativeintensity (%) 5.07 13.40 7.02 22.82 8.85 12.97 12.54 79.59 14.50 10.1815.05 14.36 16.64 100.00 16.92 13.77 18.31 27.64 20.03 20.28 20.56 15.1020.83 17.87 21.59 10.93 22.59 11.52 24.44 9.45 24.57 10.01 25.06 5.6325.74 34.24 26.22 13.36 26.43 7.29 27.07 9.21 27.97 7.49 28.25 7.4430.85 5.62

In yet another embodiment, Form II of compound of formula (II) ischaracterized by the Fourier Transform Infrared Spectroscopy (FT-IR)pattern as shown in FIG. 4.

In another embodiment, the present invention relates to crystalline formof compound of formula (II) which is designated as Form III.

In yet another embodiment, Form III of compound of formula (II) ischaracterized by the X-Ray Powder Diffraction (XRPD) pattern as shown inFIG. 5.

In yet another embodiment, Form III of compound of formula (II) isfurther characterized by the characteristic X-ray diffraction patterncomprising of the following peaks expressed in terms of 2θ±0.2: 13.92,31.01, 35.13 and 38.54.

In yet another embodiment, Form III of compound of formula (II) isfurther characterized by the characteristic X-ray diffraction patterncomprising of the following peaks expressed in terms of 2θ±0.2: 7.00,12.60, 13.92, 16.71, 20.89, 24.55, 31.01, 35.13 and 38.54.

In yet another embodiment, Form III of compound of formula (II) isfurther characterized by the characteristic X-ray diffraction patternpeaks expressed in terms of 20 as presented in Table 4.

TABLE 4 Prominent two theta positions and relative intensities of XRPDof Form III of compound of formula (II) Angle (2θ ± 0.2) Relativeintensity (%) 7.00 100.00 8.86 21.61 12.60 37.24 13.92 11.19 14.53 21.7715.10 64.50 16.71 41.21 17.62 11.10 18.31 8.42 20.89 48.85 21.70 13.6522.16 12.85 22.69 6.91 23.65 3.55 24.55 20.52 25.29 5.10 25.83 8.9226.55 9.56 27.18 6.86 27.94 15.23 31.01 5.22 35.13 6.07 38.54 5.67

In yet another embodiment, Form III of compound of formula (II) ischaracterized by the Fourier Transform Infrared Spectroscopy (FT-IR)pattern as shown in FIG. 6.

In another embodiment, the present invention relates to an amorphousform of compound of formula (II).

In yet another embodiment, amorphous form of compound of formula (II) ischaracterized by the X-Ray Powder Diffraction (XRPD) pattern as shown inFIG. 7.

In another aspect, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form I.

The process to prepare Form I comprises taking the compound of formula(II) in a mixture of diethyl ether and methanol. Alternatively, thecompound of formula (II) can be taken in a mixture of methyl tert-butylether and methanol. Preferably, the compound of formula (II) can betaken in the mixture of solvent under inert atmosphere. The reactionmass may be stirred at a suitable temperature for a suitable period oftime. The suitable temperature may be about 20 to 40° C., preferablyabout 25 to 30° C. The suitable period may be up to 5 hours, preferablyabout 1-2 hours. The solid may be collected by methods includingdecantation, centrifugation, gravity filtration, suction filtration, orany other technique for the isolation of solids. In a preferredembodiment, the solid may be filtered and washed with diethyl ether ormethyl tert-butyl ether.

The recovered solid may be optionally further dried. Drying may becarried out in a tray dryer, vacuum oven, air oven, fluidized bed drier,spin flash dryer, flash dryer, or the like. The drying may be carriedout at atmospheric pressure or under a reduced pressure at suitabletemperatures as long as the compound of formula (II) is not degraded inquality. The drying may be carried out for any desired time until therequired purity limit of LOD is achieved. For example, it may vary fromabout 1 to about 10 hours or longer.

In another aspect, the present invention relates to process forpreparing crystalline form of compound of formula (II) which isdesignated as Form II.

The process to prepare Form II comprises heating the compound of formula(II) to melt by external heating source such as heating mantle. Thetemperature for heating may be about 150-300° C., preferably about 200°C. The reaction mass may be cooled slowly to a suitable temperature toobtain crystalline form of compound of formula (II) which is designatedas Form II. The suitable temperature to which the reaction mass may becooled may be in the temperature range of 20-50° C., preferably 25-30°C.

Alternatively, crystalline form of compound of formula (II) which isdesignated as Form II can be obtained by the process, which processcomprises taking the compound of formula (II) in ethyl acetate. Thecompound of formula (II) may also be taken in a mixture of ethyl acetateand methanol. Preferably, the compound of formula (II) can be taken inthe solvent or mixture of solvents under inert atmosphere. The reactionmass may be stirred at a suitable temperature for a suitable period oftime. The suitable temperature may be about 20 to 40° C., preferablyabout 25 to 30° C. The suitable period may be up to 5 hours, preferablyabout 1-2 hours. The solid may be collected by methods includingdecantation, centrifugation, gravity filtration, suction filtration, orany other technique for the isolation of solids. The recovered solid maybe optionally further dried. Drying may be carried out in a tray dryer,vacuum oven, air oven, fluidized bed drier, spin flash dryer, flashdryer, or the like. The drying may be carried out at atmosphericpressure or under a reduced pressure at suitable temperatures as long asthe compound of formula (II) is not degraded in quality. The drying maybe carried out for any desired time until the required purity isachieved. For example, it may vary from about 1 to about 10 hours orlonger.

In another aspect, the present invention relates to a process forpreparing crystalline form of compound of formula (II) which isdesignated as Form III.

The process to prepare Form III comprises taking the compound of formula(II) in tetrahydrofuran. Preferably, the compound of formula (II) can betaken in the solvent under inert atmosphere. The reaction mass may bestirred at a suitable temperature. The suitable temperature may be about20 to 40° C., more preferably about 25 to 30° C. The reaction mass maybe stirred for a suitable period of time. The suitable period may be upto 1 hour, preferably about 10-15 minutes. To the reaction mixture, anon-polar solvent may be added. The non-polar solvent may be anyhydrocarbon solvent such as n-heptane, n-hexane or n-pentane. Thereaction mixture may be further stirred at a suitable temperature forsuitable period of time. The suitable temperature may be about 20 to 40°C., more preferably about 25 to 30° C. The suitable period may be up to10 hours, preferably about 3-4 hours. The solid may be collected bymethods including decantation, centrifugation, gravity filtration,suction filtration, or any other technique for the isolation of solids.In a preferred embodiment, the solid may be filtered and washed withn-heptane. The isolated solid may be optionally further dried. Dryingmay be carried out in a tray dryer, vacuum oven, air oven, fluidized beddrier, spin flash dryer, flash dryer, or the like. The drying may becarried out at atmospheric pressure or under a reduced pressure atsuitable temperatures as long as the compound of formula (II) is notdegraded in quality. The drying may be carried out for any desired timeuntil the required purity limit of LOD is achieved. For example, it mayvary from about 1 to about 10 hours or longer.

In another aspect, the present invention relates to a process forpreparing compound of formula (II) in amorphous form.

The process comprises heating the compound of formula (II) to melt byexternal heating device such as heating mantle. The temperature forheating may be about 150-300° C., preferably about 200° C. The reactionmass may be cooled rapidly to a suitable temperature to obtain thecompound of formula (II) in amorphous form. The suitable temperature towhich the compound may be cooled may be in the temperature range of20-50° C., preferably 25-30° C.

In another aspect of the invention, there is provided a pharmaceuticalcomposition comprising an excipients, carriers, diluents or mixturethereof, and therapeutically acceptable amount of crystalline compoundof formula (II) designated as Form (I).

In another embodiment of the invention, there is provided a method oftreating diseases, conditions and/or disorders modulated by mPGES-1enzyme; comprising administering a crystalline form of compound offormula (II) designated as Form (I), or a pharmaceutical compositionthat comprises the crystalline form of compound of formula (II)designated as form (I) along with pharmaceutically acceptableexcipients.

In another embodiment of the invention, there is provided apharmaceutical composition comprising an excipients, carriers, diluentsor mixture thereof, and therapeutically acceptable amount of crystallinecompound of formula (II) designated as Form (II).

In another embodiment of the invention, there is provided a method oftreating diseases, conditions and/or disorders modulated by mPGES-1enzyme; comprising administering a crystalline form of compound offormula (II) designated as Form (II), or a pharmaceutical compositionthat comprises the crystalline form of compound of formula (II)designated as form (II) along with pharmaceutically acceptableexcipients.

In another embodiment of the invention, there is provided apharmaceutical composition comprising an excipients, carriers, diluentsor mixture thereof, and therapeutically acceptable amount of crystallinecompound of formula (II) designated as Form (III).

In another embodiment of the invention, there is provided a method oftreating diseases, conditions and/or disorders modulated by mPGES-1enzyme; comprising administering a crystalline form of compound offormula (II) designated as Form (III), or a pharmaceutical compositionthat comprises the crystalline form of compound of formula (II)designated as form (III) along with pharmaceutically acceptableexcipients.

In another embodiment, the present invention pertains to a method oftreating diseases or conditions or disorders associated with mPGES-1enzyme, which are selected from inflammation, asthma, chronicobstructive pulmonary disease, pulmonary fibrosis, inflammatory boweldisease, irritable bowel syndrome, pain, inflammatory pain, chronicpain, acute pain, fever, migraine, headache, low back pain,fibromyalgia, myofascial disorders, viral infections, influenza, commoncold, herpes zoster, hepatitis C, AIDS, bacterial infections, fungalinfections, dysmenorrhea, burns, surgical or dental procedures,malignancies hyperprostaglandin E syndrome, classic Bartter syndrome,synovitis, atherosclerosis, gout, arthritis, osteoarthritis, juvenilearthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis,rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemiclupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis,conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis,eczema, psoriasis, stroke, diabetes mellitus, cancer, neurodegenerativedisorders such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis and multiple sclerosis, autoimmune diseases, allergicdisorders, rhinitis, ulcers, mild to moderately active ulcerativecolitis, familial adenomatous polyposis, coronary heart disease, andsarcoidosis by administering crystalline compound of formula (II)designated as Form (I), Form (II) or Form (III).

In yet another embodiment, the present invention pertains to a method oftreating diseases or conditions or disorders associated with mPGES-1enzyme, which is selected from of pain, chronic pain, acute pain,rheumatoid arthritis pain or osteoarthritic pain by administeringcrystalline compound of formula (II), designated as Form (I), Form (II)or Form (III), in therapeutically effective amount.

In yet another embodiment, the present invention pertains to a method oftreating pain, chronic pain, acute pain, rheumatoid arthritis pain orosteoarthritic pain by administering crystalline compound of formula(II), designated as Form (I), Form (II) or Form (III), intherapeutically effective amount.

In yet another embodiment, the present invention pertains to a method oftreating inflammation, neurodegenerative disorders such as Parkinson'sdisease, Alzheimer's disease and amyotrophic lateral sclerosis byadministering crystalline compound of formula (II), designated as Form(I), Form (II) or Form (III), in therapeutically effective amount.

In another embodiment, there is provided process for the preparation ofcompound of formula (II) which process comprises the steps as shown inthe scheme 1.

The process to prepare compound of formula (II) comprises:

-   -   a) reacting 2-chloro benzoic acid with        2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain        substantially pure compound of formula (VI);

-   -   b) converting compound of formula (VI) to compound of formula        (IV);

-   -   c) reacting compound of formula (IV) with oxalyl chloride and        compound of formula (V)

to obtain compound of formula (III)

and

-   -   d) converting compound of formula (III) to compound of formula        (II)

Step (a) involves reacting 2-chloro benzoic acid with2,2,2-trifluoro-N-(hydroxymethyl)acetamide to obtain compound of formula(VI). The reaction may be carried out in presence of an acid. The acidmay be inorganic or organic acid. Preferably, the acid may be inorganicacid. More preferably, the acid is sulphuric acid (H₂SO₄). The reactionmay be carried out at a suitable temperature. The suitable temperaturemay be about 20-50° C., preferably 25-30° C.

After the completion of the reaction, the reaction mass may be pouredinto water to obtain a solid product, which may be filtered and dried.The solid product may be further purified by taking the product in asuitable solvent or mixture of solvents thereof. The suitable solventmay include, but not limited to, hydrocarbon solvents such as toluene,xylene, n-heptane, cyclohexane and n-hexane and/or ether solvent such asmethyl ethyl ketone. Preferably, the suitable solvent(s) is tolueneand/or methyl ethyl ketone. The mixture may be optionally heated till aclear solution is obtained. The clear solution may be cooled to obtainthe solid which may be filtered and dried. The purification step may befurther repeated to obtain a product of desired purity.

Step (b) involves converting compound of formula (VI) to compound offormula (IV).

The compound of formula (VI) is treated with an activating agent to formits activated carboxylic acid derivative, followed by treatment with asource of ammonia to obtain compound of formula (IV).

In an embodiment, the compound of formula (VI) may be first treated withan activating agent to form its activated carboxylic acid derivative.The activating agent includes, but not limited to, oxalyl chloride,thionyl chloride, phosphorous trichloride, phosphorous pentachloride andthe like. Preferably the activating agent is oxalyl chloride. Thereaction of compound of formula (VI) with an activating agent may becatalysed by adding a suitable reagent such as DMF or triethyl amine. Inan embodiment, the catalysing reagent is DMF. The reaction may becarried out in a suitable solvent. The suitable solvent may be a polarsolvent. Preferably the solvent is tetrahydofuran. In anotherembodiment, the reaction mixture may be stirred at a suitabletemperature for a suitable period of time. The suitable temperature maybe about 25-30° C. The suitable time period may be 2-4 hours. After thecompletion of the reaction, the reaction mass may be subjected toevaporation to distil out the excess of solvent to obtain activatedcarboxylic acid derivative of compound of formula (VI).

The activated carboxylic acid derivative of compound of formula (VI) maybe further treated with a source of ammonia to obtain compound offormula (IV). The source of ammonia includes, but not limited to,formamide, ammonia gas, aqueous ammonia, alcoholic ammonia and the like.Preferably the source of ammonia is ammonia gas. The reaction may becarried out in any polar solvent. Preferably the solvent istetrahydofuran. In an embodiment, the ammonia gas may be purged in thereaction mixture. The reaction mixture may be stirred at a suitabletemperature for a suitable period of time. The suitable temperature maybe about 25-30° C. The suitable period of time may be 1-2 hours. Thereaction mixture may be maintained at a suitable pH. The suitable pH maybe about 7-9.

After the completion of the reaction, the reaction may be quenched withwater, and the reaction mass may be extracted with a suitable solvent.The suitable solvent for extraction may be ethyl acetate. The organiclayer may be dried and evaporated to dryness to obtain a product. Theproduct obtained may be taken in a non-polar solvent and stirred. Thenon-polar solvent may be any hydrocarbon solvent. Preferably the solventis cyclohexane. The product may be filtered and dried to obtain thecompound of formula (IV).

Step (c) involves reacting compound of formula (IV) with oxalyl chlorideand compound of formula (V) to obtain compound of formula (III).

The compound of formula (IV) may be first reacted with oxalyl chloride.The reaction may be carried out in a halogenated solvent. Thehalogenated solvent may be methylene dichloride, ethylene dichloride,chloroform or carbon tetrachloride. Preferably the halogenated solventis methylene dichloride. The reaction mixture may be heated to asuitable temperate for a suitable period of time. The suitabletemperature may be about 45-50° C. The suitable time period may be 4-24hours. The excess solvent in the reaction mixture may be evaporatedunder the reduced pressure to obtain a residue. A solution of compoundof formula (V) in a halogenated solvent may be added to the residue. Thehalogenated solvent may methylene dichloride, ethylene dichloride,chloroform or carbon tetrachloride. Preferably the halogenated solventis methylene dichloride. The reaction mixture may be stirred at asuitable temperature for a suitable period of time. In anotherembodiment, the temperature of the reaction may be about 15-20° C. Inyet another embodiment the reaction may be stirred for about 4-6 hours.

The reaction mixture may be further treated with an acid. The acid maybe an organic acid. Preferably the organic acid is trifluoroacetic acid.The reaction mixture may be stirred at a suitable temperature for asuitable period of time. The suitable temperature may be about 25-30° C.The suitable time period may be about 15-20 hours. After the completionof the reaction, a suitable solvent may be added to the reactionmixture. The suitable solvent may be a non-polar solvent. The non-polarsolvent may be any hydrocarbon solvent. Preferably the hydrocarbonsolvent is cyclohexane. The reaction mixture may be maintained at asuitable temperate for a suitable period of time. The suitabletemperature may be about 25-30° C. The suitable time period may be 1-2hours. The precipitate obtained may be filtered and dried to obtaincompound of formula (III). Optionally, the product may be further takenin a suitable solvent to obtain a clear solution. The suitable solventmay be any polar solvent. Preferably, the polar solvent istetrahydrofuran. The temperature range for the process may be about65-70° C. Another suitable non-polar solvent may be charged to the clearsolution. The suitable solvent may be a non-polar solvent. The non-polarsolvent may be any hydrocarbon solvent. Preferably the hydrocarbonsolvent is cyclohexane. The solution may be cooled to room temperatureand the product precipitated may be filtered and washed with a suitablenon-polar solvent such as cyclohexane to obtain compound of formula(III). The purification step may be further repeated to obtain theproduct of desired purity.

The compound of formula (V) may be prepared by reacting4-(trifluoromethyl)phenylhydrazine or its suitable salt such ashydrochloride with di tert butyl dicarbonate. The hydrazine compound maybe taken in a suitable solvent or mixture of solvents in which thecompound is soluble. The suitable solvent may be water and polarsolvent. Preferably the polar solvent is tetrahydrofuran. The reactionmay be carried out in presence of mixture of water and tetrahydrofuran.The reaction may be carried out in the presence of a suitable base. Thesuitable base may be any inorganic base. The inorganic base may besodium carbonate, potassium carbonate or lithium carbonate. Preferably,the inorganic base is sodium carbonate.

The reaction mixture may be stirred at a suitable temperature for asuitable period of time. The suitable temperature of the reaction may beroom temperature (25-30° C.). The suitable period of time may be about5-7 hours. The reaction mixture may be extracted with suitable solvent.The suitable solvent may be ethyl acetate. The organic layer may bedried and evaporated to dryness to obtain a product. The productobtained may be taken in a non-polar solvent. The non-polar solvent maybe any hydrocarbon solvent. Preferably the solvent is cyclohexane. Theproduct may be filtered and dried to obtain compound of formula (V).Optionally the product may be further washed with another solvent suchas pentane to obtain the desired purity.

Step (d) involves reacting compound of formula (III) with pivaloylhalide to obtain compound of formula (II). In an embodiment, compound offormula (III) may be reacted with pivaloyl chloride. The reaction may becarried out in the presence of a suitable base. The suitable base may beany inorganic base. The inorganic base may be sodium hydroxide,potassium hydroxide or lithium hydroxide. Preferably, the inorganic baseis sodium hydroxide. The reaction may be carried out in a suitablesolvent or mixture of solvents. The suitable solvent may be water andany polar solvent. Preferably the polar solvent is tetrahydrofuran. Thereaction may be carried out in presence of mixture of tetrahydrofuranand water.

In an embodiment, the compound of formula (III) may be first treatedwith the base at a suitable temperature. The suitable temperature may be0-5° C. The reaction mass be stirred at a suitable temperature for asuitable period of time. The suitable temperature may be about 10-20° C.The suitable period may be 1-2 hour(s). The reaction mixture may becooled to a suitable temperature and pivaloyl halide is added to itslowly. The suitable temperature may be 0-5° C. The reaction mass may bemaintained at a suitable temperature for a suitable period of time. Thesuitable temperature may be about 0-5° C. The suitable period may be30-60 minutes. To the reaction mixture conc. HCl or 10% NaOH solutionmay be optionally added to adjust the pH at 6-7 and the reaction mixturemay be further stirred. The product precipitated may be filtered toobtain compound of formula (II). Optionally, the compound of formula(II) may be purified using another suitable solvent. The suitablesolvent may be IPA. The compound and solvent mixture may be heated toobtain a clear solution. The solution may be cooled, precipitateobtained may be filtered and dried to obtain compound of formula (II)with enhanced purity. The purification step may be further repeated toobtain the desired purity.

In yet another aspect of the application there is provided process forpreparation of compound of formula (II)

from compound of formula (III)

In an embodiment, there is provided process for preparation of compoundof formula (II), which process comprises reacting compound of formula(III) with pivaloyl halide to obtain compound of formula (II).

In an embodiment, the compound of formula (III) may be reacted withpivaloyl chloride. The reaction may be carried out in presence of asuitable base. The suitable base may be an inorganic base. The inorganicbase may be sodium hydroxide, potassium hydroxide or lithium hydroxide.Preferably, the inorganic base is sodium hydroxide. The reaction may becarried out in a suitable solvent or mixture of solvents. The suitablesolvent may be water and polar solvent. Preferably the polar solvent istetrahydrofuran. The reaction may be carried out in presence of waterand tetrahydrofuran.

In another embodiment, the compound of formula (III) may be firsttreated with the water and base at a suitable temperature. The suitabletemperature may be 0-5° C. The reaction mass be stirred at a suitabletemperature for a suitable period of time. The suitable temperature maybe about 10-20° C. The suitable period may be 1-2 hour(s). The reactionmixture may be cooled to a suitable temperature and pivaloyl halide maybe added to it slowly. The suitable temperature may be 0-5° C. Thereaction mass be maintained at a suitable temperature for a suitableperiod of time. The suitable temperature may be about 0-5° C. Thesuitable period may be 30-60 minutes. To the reaction mixture conc. HClor 10% NaOH solution may be optionally added to adjust the pH at 6-7 andthe reaction mixture may be further stirred. The product precipitatedmay be filtered and dried to obtain compound of formula (II).Optionally, the compound of formula (II) may be purified using asuitable solvent. The suitable solvent may be IPA. The compound andsolvent mixture may be heated to obtain a clear solution. The solutionmay be cooled, precipitate obtained may be filtered and dried to obtaincompound of formula (II) with enhanced purity. The purification step maybe further repeated to obtain the desired purity.

In yet another embodiment, there is provided a process for preparationof compound of formula (II), which process comprising reacting compoundof formula (IV)

with oxalyl chloride and compound of formula (V)

to obtain compound of formula (III).

In an embodiment, the process involves reacting compound of formula (IV)with oxalyl chloride followed by reaction with compound of formula (V).

In another embodiment, the compound of formula (IV) may be first treatedwith oxalyl chloride. In this embodiment the reaction may be carried attemperature about 45-50° C. In another embodiment, the reaction may bestirred for 4-5 hours. The reaction may be carried in a halogenatedsolvent. The halogenated solvent may methylene dichloride, ethylenedichloride, chloroform or carbon tetrachloride. Preferably thehalogenated solvent is methylene dichloride. The excess solvent in thereaction mixture may be evaporated under the reduced pressure to obtaina residue. A solution of compound of formula (V) in a suitable solventmay be added to the above reaction mixture. The suitable solvent may bea halogenated solvent. The halogenated solvent may be methylenedichloride, ethylene dichloride, chloroform or carbon tetrachloride.Preferably the halogenated solvent is methylene dichloride. The reactionmixture may be further stirred at a suitable temperature for a suitableperiod of time. In this embodiment, the temperature of the reaction maybe about 15-20° C. and the reaction may be stirred for about 4-6 hours.

The reaction mixture may be further treated with an acid. The acid maybe an organic acid. Preferably the organic acid is trifluoroacetic acid.The reaction mixture may be stirred at a suitable temperature foranother suitable period of time. The suitable temperature may be about25-30° C. The suitable time period may be about 15-20 hours. After thecompletion of the reaction, a suitable solvent may be added to thereaction mixture. The suitable solvent may be a non-polar solvent. Thenon-polar solvent may be any hydrocarbon solvent. Preferably thehydrocarbon solvent is cyclohexane. The reaction may be maintained at asuitable temperate for a suitable period of time. The suitabletemperature may be about 25-30° C. The suitable period of time may be1-2 hours. The precipitate obtained may be filtered and dried to obtaincompound of formula (III). Optionally, the product may be further takenin a suitable solvent to obtain a clear solution. The suitable solventmay be any polar solvent. Preferably, the polar solvent istetrahydrofuran. The temperature range for the process may be 65-70° C.A suitable non-polar solvent may be charged to the clear solution. Thesuitable solvent may be a non-polar solvent. The non-polar solvent maybe any hydrocarbon solvent. Preferably the hydrocarbon solvent iscyclohexane. The solution may be cooled to room temperature and thecompound precipitated may be filtered and washed with a suitablenon-polar solvent such as cyclohexane to obtain compound of formula(III). The purification step may be further repeated to obtain thedesired purity.

The compound of formula (V) may be prepared by reacting4-(trifluoromethyl)phenylhydrazine or its suitable salt such ashydrochloride with di tert butyl dicarbonate. The hydrazine compound maybe taken in a suitable solvent or mixture of solvents in which thecompound is soluble. The suitable solvent may be water and polarsolvent. Preferably the polar solvent is tetrahydrofuran. The reactionmay be carried out in presence of mixture of water and tetrahydrofuran.The reaction may be carried out in the presence of a suitable base. Thesuitable base may be any inorganic base. The inorganic base may besodium carbonate, potassium carbonate or lithium carbonate. Preferably,the inorganic base is sodium carbonate.

The reaction mixture may be stirred at a suitable temperature for asuitable period of time. The suitable temperature of the reaction may beroom temperature (25-30° C.). The suitable period of time may be about5-7 hours. The reaction mixture may be extracted with suitable solvent.The suitable solvent may be ethyl acetate. The organic layer may bedried and evaporated to dryness to obtain a product. The productobtained may be taken in a non-polar solvent. The non-polar solvent maybe any hydrocarbon solvent. Preferably the solvent is cyclohexane. Theproduct may be filtered and dried to obtain compound of formula (V).Optionally the product may be further washed with another solvent suchas pentane to obtain the desired purity.

In another embodiment, there is provided process for preparation ofcompound of formula (II) or salt thereof, which process comprising thestep of reacting 2-chloro benzoic acid with a compound (VII)

to obtain compound of formula (VI a)

wherein R is chloro, bromo, or methyl.

In this embodiment, compound (VII) can be selected from2,2,2-Trichloro-N-(hydroxymethyl)acetamide,2,2,2-Tribromo-N-(hydroxymethyl) acetamide or2,2,2-Trimethyl-N-(hydroxymethyl)acetamide. In a further embodiment thereaction may be carried out in presence of an acid. The acid may beinorganic or organic acid. Preferably, the acid may be inorganic acid.More preferably, the acid is sulphuric acid (H₂SO₄). The reaction may becarried out at a suitable temperature. The suitable temperature may beroom temperature (25-30° C.).

After the completion of the reaction, the reaction mass may be poured incold water to obtain a compound represent by formula (VI a), which maybe filtered and dried. The compound of formula (VI a) may be furtherpurified by taking the compound in a suitable solvent or mixture thereofand optionally heating the mixture till a clear solution is obtained.The suitable solvent may include, but not limited to, hydrocarbonsolvents such as toluene, xylene, n-heptane, cyclohexane and n-hexane.Preferably, the suitable solvent is toluene and/or methyl ethyl ketone.The clear solution may be cooled to obtain the compound of formula (VIa) which may be filtered and dried. The purification step may be furtherrepeated to obtain the desired purity.

Pharmaceutical Compositions

The compounds of the invention are typically administered in the form ofa pharmaceutical composition. Such compositions can be prepared usingprocedures well known in the pharmaceutical art and comprise at leastone compound of the invention. The pharmaceutical composition of thepresent patent application comprises one or more compounds describedherein and one or more pharmaceutically acceptable excipients.Typically, the pharmaceutically acceptable excipients are approved byregulatory authorities or are generally regarded as safe for human oranimal use. The pharmaceutically acceptable excipients include, but arenot limited to, carriers, diluents, glidants and lubricants,preservatives, buffering agents, chelating agents, polymers, gellingagents, viscosifying agents, solvents and the like.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil,gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate,sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,stearic acid, lower alkyl ethers of cellulose, silicic acid, fattyacids, fatty acid amines, fatty acid monoglycerides and diglycerides,fatty acid esters, and polyoxyethylene.

The pharmaceutical composition may also include one or morepharmaceutically acceptable auxiliary agents, wetting agents, suspendingagents, preserving agents, buffers, sweetening agents, flavoring agents,colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, forexample, capsules, tablets, solutions, suspensions, injectables orproducts for topical application. Further, the pharmaceuticalcomposition of the present invention may be formulated so as to providedesired release profile.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted routes of administration of pharmaceutical compositions.The route of administration may be any route which effectivelytransports the active compound of the patent application to theappropriate or desired site of action. Suitable routes of administrationinclude, but are not limited to, oral, nasal, buccal, dermal,intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous,intraurethral, intramuscular, or topical.

Solid oral formulations include, but are not limited to, tablets,capsules (soft or hard gelatin), dragees (containing the activeingredient in powder or pellet form), troches and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsions,and sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, powders, solutions, eye or ear drops, impregnated dressings,and may contain appropriate conventional additives such aspreservatives, solvents to assist drug penetration.

The pharmaceutical compositions of the present patent application may beprepared by conventional techniques, e.g., as described in Remington:The Science and Practice of Pharmacy, 20^(th) Ed., 2003 (LippincottWilliams & Wilkins).

Suitable doses of the compounds for use in treating the diseases anddisorders described herein can be determined by those skilled in therelevant art. Therapeutic doses are generally identified through a doseranging study in humans based on preliminary evidence derived from theanimal studies. Doses must be sufficient to result in a desiredtherapeutic benefit without causing unwanted side effects. Mode ofadministration, dosage forms, and suitable pharmaceutical excipients canalso be well used and adjusted by those skilled in the art. All changesand modifications are envisioned within the scope of the present patentapplication.

Definitions

The term “crystalline” as used herein, means having a regularlyrepeating arrangement of molecules or external face planes.

The term “amorphous” as used herein, means essentially without regularlyrepeating arrangement of molecules or external face planes.

Unless stated otherwise, percentages stated throughout thisspecification are weight/weight (w/w) percentages.

The term “mixture” as used herein, means a combination of at least twosubstances, in which one substance may be completely miscible, partiallymiscible or essentially immiscible in the other substance.

The term “treating” or “treatment” of a state, disorder or conditionincludes; (a) preventing or delaying the appearance of clinical symptomsof the state, disorder or condition developing in a subject that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition; (b) inhibiting the state, disorder orcondition, i.e., arresting or reducing the development of the disease orat least one clinical or subclinical symptom thereof; or (c) relievingthe disease, i.e., causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

All powder X-ray diffraction patterns were obtained using: PanlyticalX'PERT-PRO diffractometer model and measured with Cu—Kα1 radiation atwavelength of 1.54060 A°. The obtained powder X-ray diffraction profileswere integrated using X'Pert High Score Plus Software.

It is meant to be understood that peak heights in a powder x-raydiffraction pattern may vary and will be dependent on variables such asthe temperature, crystal size, crystal habit, sample preparation orsample height in the analysis well of the Scintag×2 Diffraction PatternSystem.

All FTIR spectra were recorded using KBr on Perkin-Elmer instrument(Model: Spectrum One). The data was processed using Spectrum OneSoftware.

As used herein, the term “average particle size” (or synonymously, “meanparticle size”) refers to the distribution of particles, wherein about50 volume percent of all the particles measured have a size less thanthe defined average particle size value and about 50 volume percent ofall measurable particles measured have a particle size greater than thedefined average particle size value. This can be identified by the term“D₅₀” or “d (0.5)”.

The term “D₁₀” refers to the distribution of particles, wherein about 10volume percent of all the particles measured have a size less than thedefined particle size value. This can be identified by the term “d(0.1)”as well. Similarly, as used herein, the term “D₉₀” refers to thedistribution of particles, wherein about 90 volume percent of all theparticles measured have a size less than the defined particle sizevalue. This can be identified by the term or “d (0.9)” as well.

The average particle size can be measured using various techniques likelaser diffraction, photon correlation spectroscopy and Coulter'sprinciple. Typically, instruments like ZETASIZER® 3000 HS (Malvern®Instruments Ltd., Malvern, United Kingdom), NICOMP 388™ ZLS system(PSS-Nicomp Particle Sizing Systems, Santa Barbara, Calif., USA), orCoulter Counter are generally used to determine the mean particle size.Preferably, Mastersizer 2000 (Malvern® Instruments Ltd., Malvern, UnitedKingdom) is used to determine the particle size of the particles.

EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulphate, filtration and evaporation of the solvent.Purification, unless otherwise mentioned, includes purification bysilica gel chromatographic techniques, generally using ethylacetate/petroleum ether mixture of a suitable polarity as the mobilephase. Use of a different eluent system is indicated within parentheses.The following abbreviations are used in the text: DMSO-d₆:Hexadeuterodimethyl sulfoxide; AcOEt: ethyl acetate; equiv. or eq.:equivalents; h: hour(s); L: litres; CDCl₃: deuterated chloroform; CHCl₃:chloroform; EtOAc or EA: ethyl acetate; DCM or MDC: dichloromethane ormethylene dichloride; DMSO: dimethyl sulfoxide; DMF:N,N-dimethylformamide; MTBE: Methyl tert-butyl ether; DSC: Differentialscanning calorimetry; K₂CO₃: potassium carbonate; MeOH: methanol; EtOH:ethanol; NaHCO₃: sodium bicarbonate; Na₂CO₃: sodium carbonate; THF:tetrahydrofuran; J: Coupling constant in units of Hz; RT or rt: roomtemperature (22-30° C.); q.s.: quantity sufficient; aq.: aqueous; equiv.or eq.: equivalents; cone.: concentrated; min: minutes; i.e.: that is; hor hrs: hours.

The parameters mentioned in the description which characterize thepolymorphic nature, particle size by the measuring techniques andmethods are described below:

Particle Size Distribution Studies:

The particle size distribution was measured using Mastersizer 2000(Malvern® instruments Ltd., Malvern, United Kingdom) with followingmeasuring equipment and settings:

-   -   Instrument: Malvern Mastersizer 2000    -   Sample Handling Unit: Hydro 2000S (A)    -   Dispersant RI: 1.33    -   Dispersant: Water    -   Sample quantity: 25-50 mg    -   Measurement time: 5.0 sec

Powder X-Ray Diffraction Studies:

All powder X-ray diffraction patterns were obtained using: PanlyticalX'PERT-PRO diffractometer model and measured with Cu-Kal radiation atwavelength of 1.54060 A°. The obtained powder X-ray diffraction profileswere integrated using X'Pert High Score Plus Software.

Fourier Transform Infrared Spectroscopy (FT-IR) Studies

About 200 mg of KBr, previously dried at 200° C. and cooled, was takeninto a mortar and grinded to a fine powder. 2-3 mg of test sample wasadded to it and was mixed well and grinded to obtain a uniform sample. Asmall quantity of the sample powder was taken, put it between dies andcompressed it by applying 10-15 pound pressure to obtain asemitransparent pellet. The IR spectrum of the pellet was recorded from4000 cm⁻¹ to 450 cm taking air as a reference.

HPLC Conditions:

Apparatus: A High Performance Liquid Chromatograph equipped withquaternary gradient pumps, variable wavelength UV detector attached withdata recorder and Integrator software or equivalent.Column: Zorbax Eclipse XDB C-8, 150 mm×4.6 mm, 5 t or equivalentMobile phase: A: Buffer B: Methanol (Gradient Program)Buffer: Water, pH adjusted to 2.2 with trifluoroacetic acid solution.Filter through 0.45μ filter paper and degas.Diluent: Water: Methanol (20:80 v/v)Flow Rate: 1.0 mL/minuteDetection wavelength: UV 270 nmColumn temperature: 25° C.Injection volume: 20 μlRun time: 60 min

Test Solution:

25 mg of the compound was weighed and transferred into a 50 mLvolumetric flask. Methanol (5 ml) was added and it was sonicated todissolve. The diluent was added to make up the solution to the mark ofthe flask.

Procedure:

The equal volumes of blank (diluent) and test solution were separatelyinjected into the High Performance liquid chromatography. The responseswere recorded eliminating the peaks due to blank and the chromatographicpurity by area was calculated by normalization method.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The examples provided below aremerely illustrative of the invention and are not intended to limit thesame to disclosed embodiments. Variations and changes obvious to oneskilled in the art are intended to be within the scope and nature of theinvention.

Intermediate 1 Preparation of2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid

To a solution of 2-chlorobenzoic acid (930.0 gm, 5.96 mol) in cone.sulphuric acid (5580 ml), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide(930.0 gm, 6.0 mol) was added at 20° C. and the reaction mixture wasstirred for 15.0 h at 25-30° C. After the completion of the reaction,the reaction was slowly quenched with cold water (37.0 lit) at 10-15° C.The precipitated product was filtered and dried. The obtained productwas purified using mixture of toluene and methylethylketone (7:1×4times) to obtain 580.0 gm of the tittle compound having chemical purityof 98.0%, determined by HPLC.

Intermediate 2 Preparation of2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzamide

To a solution of 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoicacid (575.0 gm, 2.04 mol) in THF (3450.0 ml) catalytic amount of DMF(2.9 ml) was added. Oxalyl chloride (389.0 gm, 3.06 mol) was added tothe reaction mixture slowly at 20° C. The reaction mixture was stirredfor 2.0 h at 25-30° C. After the completion of the reaction, thereaction mass was distilled under reduced pressure to obtain the acidchloride derivative. THF (3450.0 ml) was added and the reaction mixturewas cooled to 0-5° C. Ammonia gas was purged to the reaction mixturetill a pH of 7-9 was obtained and the reaction mixture was stirred for1.0 h at 20-25° C. After the completion of the reaction, the reactionwas quenched with water (7.0 lit). The reaction mass was extracted withethyl acetate (2×7.0 lit). The organic layer was washed with brine. Theorganic layer was concentrated under reduced pressure. Cyclohexane (1440ml) was charged to the residue and the mixture was maintained for 1.0 hat 25-30° C. The product precipitated was filtered and dried to obtain505.0 gm of the title compound having chemical purity of 95.0%,determined by HPLC.

Intermediate 3 Preparation of tert-butyl2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate

To a solution of 4-(trifluoromethyl)phenyl]hydrazine HCl (400.0 gm, 1.88mol) in THF (2400 ml), water (1200 ml) was added. Sodium carbonate (480gm, 4.52 mol) was added to the reaction mixture slowly. The reactionmass was cooled to 10-15° C. and di-tert-butyl dicarbonate (596 gm, 2.73mol) was added slowly. The reaction mixture was stirred for 6.0 h at25-30° C. After the completion of the reaction, the reaction wasquenched with water (15.0 lit) and the reaction mass was extracted withethyl acetate (2×5.0 lit). The organic layer was washed with waterfollowed by brine. The organic layer was concentrated under reducedpressure. Cyclohexane (1.0 lit) was charged to the obtained residue andit was stirred for 1.0 h at 25-30° C. The precipitated product wasfiltered and dried to obtain 480.0 gm of the title compound havingchemical purity of 99%, determined by HPLC.

Intermediate 4 Preparation ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide

A solution of 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzamide(500 gm, 1.78 mol) in MDC (5.0 lit) was cooled to 20° C. and oxalylchloride (295 gm, 2.32 mol) was added to it slowly. The reaction mixturewas stirred at 45-50° C. for 4.0 h. The reaction mass was concentratedunder reduced pressure. A solution of tert-butyl2-[4-(trifluoromethyl)phenyl]hydrazinecarboxylate (492 gm, 1.78 mmol) inMDC (6.0 lit) was prepared separately and was added to the above residueat 15-20° C. The reaction mixture was stirred for 4.0 h. Trifluoroaceticacid (600.0 ml) was added to the reaction mixture at 10-15° C. and thereaction was stirred for 15.0 h at 25-30° C. After the completion of thereaction, cyclohexane (12.0 lit) was added to the reaction mixture andit was maintained for 1.0 h at 25-30° C. The product precipitated wasfiltered and dried to obtain 734.0 gm of the title compound havingchemical purity of 98%, determined by HPLC.

Example 1 Preparation ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

To a solution ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide(35.0 gm, 0.075 mol) in THF (175.0 ml) water (280.0 ml) was added andthe reaction mixture was cooled to 5° C. Sodium hydroxide solution(10.55 gm, 0.263 mol) in water (70.0 ml) was added slowly to thereaction mixture and it was stirred for 1.0 h at 15-20° C. The reactionmixture was cooled to 5° C. and pivaloyl chloride (13.6 gm, 0.113 mol)was added slowly. The reaction mixture was stirred for 30.0 min at sametemperature. The pH of the reaction mixture was adjusted to about 6-7 byadding 20% HCl or 20.0% sodium hydroxide solution and the reactionmixture was maintained for another 30.0 min at 10-15° C. The productprecipitated was filtered and dried to obtain 29.0 gm of the titlecompound having chemical purity of 99.5%, determined by HPLC.

Example 2 Preparation of Form (I) ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

Method 1:

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide(29.0 gm) was dissolved in 15% methanol in ethyl acetate (1450 ml) at45° C. and the reaction mixture was concentrated under the reducedpressure. To the residue obtained, 10.0% methanol in MTBE (290.0 ml) wascharged and the mixture was stirred for 1.0 h at 25-30° C. The mixturewas filtered and the filtrate was dried to obtain 25.0 gm of Form (I) ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide.

Method 2:

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (10.0 gm) was taken in a mixture of diethyl ether (60ml) and methanol (30 ml) and the reaction mixture was stirred for 2 h.The mixture was filtered and the solid was dried to obtain 7.5 gm ofForm (I) ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide.

Example 3 Preparation of Form (II) ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

Method 1:

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (1.0 gm) was heated to melt by external heating. Themass was cooled to room temperature (25-30° C.) slowly to obtain 0.90 gmof Form (II) ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide.

Method 2:

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (1.0 gm) was crystallized in ethyl acetate (5 ml) andmethanol (5 ml) to obtain 0.60 gm of Form (II) ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide.

Method 3:

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (1.0 gm) was slurred in ethyl acetate (3 ml) to obtain0.75 gm of Form (II) ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide

Example 4 Preparation of Form (III) ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (10.0 gm) was taken in THF (150 ml). The mixture wasstirred for 10-15 min at 25-30° C. to obtain clear solution. n-Heptane(500 ml) was added to the clear solution at a moderate speed in 5-10min. A solid was precipitated which was further stirred for 3-4 h. Themixture was filtered, the solid was washed with n-heptane (50 ml) and itwas dried to obtain 8.3 gm of Form (III) ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide.

Example 5 Preparation of amorphous form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide

N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide (1.0 gm) was heated to melt by external heating. Themass was cooled to room temperature (25-30° C.) rapidly to obtain 0.80gm of amorphous form ofN-(4-chloro-3-{5-oxo-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1,2,4-triazol-3-yl}benzyl)-pivalamide(>95%).

Example 6 Stability studies of compound of formula II:(N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide)

The compound of formula II was stored under conditions as shown in belowtable and a total amount of degradation products (related substances) aswell as single maximum impurity formed during storage was estimated byHPLC. The material was packed in inner clear polythene bag undernitrogen lined with black polythene bag, covered with triple laminatedaluminium bag placed in HDPE drum and subjected to the conditionsmentioned in the table 5.

TABLE 5 Storage conditions Condition 1 Condition 2 Temperature 25 ± 2°C. 40 ± 2° C. Humidity (% RH) 60 ± 5% RH 75 ± 5% RH Testing intervals 0,1, 2, 3, 6 months 0, 1, 2, 3, 6 months

The result of stability studies of compound of formula (II) carried outunder the conditions mentioned in the table 5 is presented in tables 6and 7.

Stability of Compound of Formula II Under the Storage Condition 1:

TABLE 6 Storage period (months) Test Item (%) 0 1 2 3 6 Relatedsubstances 0.13 NT NT 0.14 0.14 Single max. impurity 0.13 NT NT 0.140.14 NT: not tested

Stability of Compound of Formula II Under the Storage Condition 2:

TABLE 7 Storage period (months) Test Item (%) 0 1 2 3 6 Relatedsubstances 0.13 0.14 0.13 0.14 0.13 Single max. impurity 0.13 0.14 0.130.14 0.13

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above.

All publications and patent applications cited in this application areherein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated herein by reference.

1. A crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide(Compound formula II), structurally represented as


2. The crystalline form according to claim 1, having a characteristicX-ray diffraction pattern comprising of the peaks expressed in terms of2θ±0.2: 5.66, 6.55 and 13.05.
 3. The crystalline form according to claim1, having a characteristic X-ray diffraction pattern comprising of thepeaks expressed in terms of 2θ±0.2: 5.66, 6.55, 12.51, 13.05, 15.01,16.59 and 25.69.
 4. The crystalline form according to claim 1, having acharacteristic X-ray diffraction pattern comprising of the followingpeaks expressed in terms of 2θ±0.2: 24.57 and 30.85.
 5. The crystallineform according to claim 1, having a characteristic X-ray diffractionpattern comprising of the following peaks expressed in terms of 2θ±0.2:7.02, 12.54, 16.64, 18.31, 24.57, 25.74 and 30.85.
 6. The crystallineform according to claim 1, having a characteristic X-ray diffractionpattern comprising of the following peaks expressed in terms of 2θ±0.2:13.92, 31.01, 35.13 and 38.54.
 7. The crystalline form according toclaim 1, having a characteristic X-ray diffraction pattern comprising ofthe following peaks expressed in terms of 2θ±0.2: 7.00, 12.60, 13.92,16.71, 20.89, 24.55, 31.01, 35.13 and 38.54
 8. An amorphous form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide.
 9. The crystalline compound of formula (II) according toclaim 1, having an average particle size value (D₅₀) in the range fromabout 1 μm to about 100 μm. 10.-21. (canceled)
 22. A process forpreparation of crystalline form ofN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide,having a characteristic X-ray diffraction pattern comprising of thepeaks expressed in terms of 2θ±0.2: 5.66, 6.55, and 13.05, which processcomprises the following steps: a) takingN-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamidein a mixture of diethyl ether and methanol or in a mixture of methyltert-butyl ether and methanol; b) stirring the mixture of step (a); andc) isolating the desired compound. 23.-30. (canceled)